ABSTRACT

Context.— High-dose iodine 131 is the treatment of choice in the United States
for most adults with hyperthyroid disease. Although there is little evidence
to link therapeutic 131I to the development of cancer, its extensive
medical use indicates the need for additional evaluation.

Setting.— Twenty-five clinics in the United States and 1 clinic in England.

Patients.— A total of 35,593 hyperthyroid patients treated between 1946 and 1964
in the original Cooperative Thyrotoxicosis Therapy Follow-up Study; 91% had
Graves disease, 79% were female, and 65% were treated with 131I.

Results.— Of the study cohort, 50.5% had died by the end of follow-up in December
1990. The total number of cancer deaths was close to that expected based on
mortality rates in the general population (2950 vs 2857.6), but there was
a small excess of mortality from cancers of the lung, breast, kidney, and
thyroid, and a deficit of deaths from cancers of the uterus and the prostate
gland. Patients with toxic nodular goiter had an SMR of 1.16 (95% confidence
interval [CI], 1.03-1.30). More than 1 year after treatment, an increased
risk of cancer mortality was seen among patients treated exclusively with
antithyroid drugs (SMR, 1.31; 95% CI, 1.06-1.60). Radioactive iodine was not
linked to total cancer deaths (SMR, 1.02; 95% CI, 0.98-1.07) or to any specific
cancer with the exception of thyroid cancer (SMR, 3.94; 95% CI, 2.52-5.86).

Conclusions.— Neither hyperthyroidism nor 131I treatment resulted in a
significantly increased risk of total cancer mortality. While there was an
elevated risk of thyroid cancer mortality following 131I treatment,
in absolute terms the excess number of deaths was small, and the underlying
thyroid disease appeared to play a role. Overall, 131I appears
to be a safe therapy for hyperthyroidism.

Figures in this Article

HYPERTHYROID DISEASE is relatively common, particularly among women.
The incidence of Graves disease, the cause of over 80% of hyperthyroidism
in the United States, is between 0.02% and 1%.1- 3
Hyperthyroidism can be treated with radioiodine (iodine 131), surgery (subtotal
thyroidectomy), or antithyroid drugs, but 131I is the treatment
of choice for most adults in the United States.4
The extensive use of 131I therapy has raised concern regarding
its potential carcinogenic and leukemogenic effects, although there is little
evidence to support this concern.5- 9
Public interest in the late health effects of 131I exposure was
rekindled by the 1986 Chernobyl accident and acknowledgment of past 131I releases from nuclear reactors and bomb testing.

The Cooperative Thyrotoxicosis Therapy Follow-up Study began in 1961.
It included 35609 patients with hyperthyroidism treated between 1946 and 1964
at one of 26 study clinics. When the study ended in 1968, after a mean follow-up
of 8.2 years, thyroid cancer incidence and mortality10
and leukemia incidence5 were not significantly
elevated in the 131I-treated patients compared with other patients.
In a more recent follow-up of patients from the Mayo Clinic, Rochester, Minn,
and Massachusetts General Hospital, Boston, total cancer mortality was not
associated with131 I therapy.11,12
However, the incidence of cancers in organs that concentrate iodine was elevated
(relative risk [RR], 1.8; 95% confidence interval [CI], 1.1-3.2) among the 131 I-treated patients at the Mayo Clinic,13
and breast cancer incidence was slightly increased (RR, 1.3; 95% CI, 0.8-1.9)
in the Massachusetts General Hospital patients.14
Although no association between 131I exposure and mortality from
leukemia (standardized mortality ratio [SMR], 0.98; 95% CI, 0.64-1.42) or
breast cancer (SMR, 0.86; 95% CI, 0.69-1.02) was seen among Swedish hyperthyroid
patients, a significant excess of respiratory (SMR, 1.26; 95% CI, 1.04-1.49)
and digestive (SMR, 1.14; 95% CI, 1.03-1.25) cancer mortality was observed.
During the first 10 years of follow-up, there was an excess of thyroid cancer
mortality (SMR, 3.22; 95% CI, 1.54-5.98), which completely disappeared after
10 years (SMR, 0.66; 95% CI, 0.08-2.37).15 To
assess the long-term carcinogenic effects of treatment for hyperthyroidism,
we conducted a mortality follow-up, through 1990, of the original Cooperative
Thyrotoxicosis Therapy Follow-up Study population.

METHODS

The original Cooperative Thyrotoxicosis Therapy Follow-up Study included
all hyperthyroid patients treated with 131I, thyroid surgery, antithyroid
drugs, or any combination of these treatments, between January 1, 1946, and
December 31, 1964, at 25 US and 1 British medical center (Table 1). Comprehensive clinical data were abstracted from medical
records and hyperthyroidism was classified as Graves disease in 91% of the
patients, toxic nodular goiter in 8%, and unknown in 1%. Forty percent of
the patients were known to have received some treatment for hyperthyroidism
prior to study entry; 75% of these patients had received antithyroid drugs
only, 22% had undergone thyroidectomy alone or in combination with antithyroid
drugs, and 2% had received 131 I therapy with or without other
treatments. Follow-up information was obtained from the treating physician
or clinic or from the patient when no medical source was available. At the
end of the first follow-up, 6228 patients (17.5%) had died and 1432 (4.0%)
were lost to follow-up. The original study methods have been described by
Saenger et al,5 Dobyns et al,10
Becker et al,16 and Tompkins.17

Using computer lists, microfiche, microfilm cassettes, and handwritten
material, a master file of 35630 patients from the original study was assembled
in 1984 (Figure 1). The National
Cancer Institute worked with 4 regional study centers, Harvard University,
Boston, Memorial Sloan-Kettering Cancer Center, New York, NY, University of
Southern California, Los Angeles, and Research Triangle Institute, Research
Triangle Park, NC, to conduct a second mortality follow-up of the study cohort.
Follow-up was not attempted for 4010 patients, including 1414 patients from
3 small treatment centers not in the geographical areas of the other centers
and 2596 patients whose names had been removed from the medical records by
the treatment clinics after completion of the first study. The exclusion of
these patients from further follow-up was due to technical reasons and was
in no way related to patient characteristics. With these exclusions, 31620
patients were eligible for further follow-up. Since 6228 patients were known
to have died during the first follow-up, 25392 patients remained to be traced.
After supplemental identification data were abstracted, study subjects were
traced using records from the National Death Index, Health Care Financing
Administration, Social Security Administration, state vital statistics offices,
state motor vehicle administrations, local tracing resources, and commercial
tracing companies. Copies of death certificates were obtained for deceased
patients and were coded according to the International Classification
of Diseases, Eighth Edition (ICD-8).18 Causes of death from the first study were recoded
from the International Classification of Diseases, Seventh
Edition (ICD-7)19
to ICD-8 by trained nosologists. After final editing
of the data tape, 35593 patients were included in the study cohort.

In the main analyses, we compared the observed number of deaths with
the expected number based on US national mortality rates. Person-years at
risk were computed for each patient from the date of study entry (the first
time a patient visited a participating study clinic during the study enrollment
period) until the date of death, the date last known to be alive for those
lost to follow-up, or the end of follow-up (December 31, 1990) for those known
to be alive. Standardized mortality ratios (the ratio of observed to expected
number of deaths) and 95% CIs were computed assuming a Poisson distribution
for the observed number. Cause-specific expected numbers of deaths were calculated
by applying the age-, sex-, race-, and calendar-year–specific mortality
rates to the appropriate person-years at risk.20
Because we were using US mortality rates as the comparison population, the
1699 patients from England had to be excluded from these analyses. In addition,
we excluded 146 patients for whom information on sex, date of birth, or date
of study entry was missing, leaving 33748 patients.

The SMR analyses were performed separately for patients with Graves
disease and toxic nodular goiter and for 7 treatment categories: 131I treatment only; 131 I treatment and surgery; 131I
treatment and drugs; 131 I treatment, surgery, and drugs; surgery
only; surgery and drugs; and drugs only. Because results were virtually the
same for the 4 groups of patients treated with 131I and for the
2 surgery groups, we present results for combined treatment groups. Dates
of onset of treatment were unknown for patients receiving drug therapy; however,
since 98% of the 131I-treated patients and 78% of patients who
underwent surgery received their first treatment within 2 years of study entry,
study entry date was used as a surrogate date for evaluation of latency. Only
231 patients had surgery before 131 I treatment. Since deaths occurring
within 1 year of study entry are not likely to be caused by treatment for
hyperthyroidism, these deaths were excluded in all analyses related to treatment.
As in all mortality analyses using US national mortality rates as a comparison,
patients with preexisting cancers were not excluded because they are included
in the national rates.

Doses from 131I to 17 organs were estimated for study subjects
by multiplying the amount of administered activity by the dose factors (age
[1, 5, 10, 15, and >15 years old], and 24-hour thyroid uptake [0%, 25%, 35%,
45%, and 55%]) provided for each organ in current International Commission
on Radiological Protection tables.21 Fewer than
500 patients were aged 15 years or younger and most patients (70%) had at
least one 24-hour thyroidal 131 I uptake greater than 55%. Because
many clinics treated all patients with a standard amount of administered activity,
thyroid uptake measurements were not performed before treatment. We estimated
these uptakes using the experience of the 3162 uptakes performed within 1
month prior to treatment, modeled on sex, age at treatment, number of treatments,
calendar year of treatment, clinic, type of hyperthyroidism, and administered
activity of 131I. We did not estimate dose to the thyroid because
gland size, dose distribution, and effective half-life must be known. However,
at least 50 to 70 Gy delivered to the thyroid is usual when treating hyperthyroidism.22 Only 3 other organs received an average 131
I dose above 100 mGy: stomach (178 mGy), bladder (128 mGy), and small intestine
(108 mGy). The average estimated dose to the red bone marrow was 42 mGy and
to the breast was 32 mGy. Using a different method of estimation, Saenger
et al5 reported the mean bone marrow dose to
be between 80 and 160 mGy. Their estimate is 2 to 4 times higher than ours,
probably because based on information from the literature at that time,23,24 they assumed that the blood dose was
1.7 times the administered activity and that the bone marrow dose was between
46% and 86% of the blood dose. More recently, Zanzonico et al25
reconstructed doses for 468 patients from the original study group and their
results were similar to ours: for patients with Graves disease, average doses
to the bladder, red bone marrow, and breast were 190 mGy, 50 mGy, and 30 mGy,
respectively. To ensure that the imputed uptakes did not significantly affect
the analyses, we also estimated doses assuming all unknown uptakes to be 25%
and 55% (the lower and upper limits used in the International Commission on
Radiological Protection tables). Dose estimates based on 55% uptakes were
similar to those based on the imputed uptakes. When 25% uptakes were assumed,
dose estimates were somewhat lower, but few hyperthyroid patients would have
uptakes below 50%.

Because of particular interest in thyroid, hematopoietic, and lymphoproliferative
malignancies, we used Poisson regression methods for analysis of grouped cohort
time-to-exposure data to evaluate the relationship between deaths from hematopoietic
and lymphoproliferative malignancies and 131I administered activity,
as well as estimated absorbed bone marrow dose. For thyroid mortality, we
could only assess administered activity of 131I because we were
unable to estimate organ doses. Since these analyses did not use an external
comparison, we included the patients from England, but excluded patients with
cancers diagnosed before study entry. The data were cross-classified by sex,
age at treatment (0-29, 30-39, 40-49, 50-59, and ≥60 years), time since
treatment (0-4, 5-9, 10-19, and ≥20 years), type of hyperthyroidism (Graves
disease, toxic nodular goiter), administered 131I activity (0,
0.01-4, 5-6, 7-9, 10-14, 15-19, and ≥20 mCi), and for the analysis of hematopoietic
and lymphoproliferative malignancies, red bone marrow dose estimates (0, 0.1-14,
15-19, 20-24, 25-29, 30-39, 40-49, 50-79, and ≥80 mGy). We fit a linear
excess RR dose-response model (the background disease rate among the nonexposed×[1+the
excess RR]), taking the described covariates into consideration. Background
rates were stratified by sex, age at treatment, time since treatment, and
type of hyperthyroidism. Maximum likelihood parameter estimates were obtained,
and likelihood ratio tests were used to assess the significance of the dose
response.26 Trend tests were calculated using 131I exposure as a continuous variable. EPICURE software (HiroSoft International
Corp, Seattle, Wash) was used for these analyses.27

RESULTS

At the end of follow-up, the 35593 study subjects (79% female) had 738831
person-years of follow-up. The mean age at study entry was 46 years and 3%
were younger than 20 years. There were 10760 patients (30.2%) still alive,
17959 (50.5%) were deceased, and 6874 (19.3%) were lost to follow-up. Eighty-eight
percent of the study population had 5 to 10 years of follow-up and 76% had
10 years or more. The mean length of follow-up from first clinic visit was
21 years (range, 1-44 years). Overall follow-up was better for men (83% vs
79% for women), older patients (86% for those ≥50 years at study entry
vs 77% for those <50 years), and patients treated with surgery (88% vs
78% for 131I and 75% for drug treatment). The difference by treatment
group is due to the low proportion of surgery patients (13%) in the group
of 4010 patients for whom follow-up was not conducted for technical reasons.
There were no differences in follow-up by treatment among the 31620 patients
for whom follow-up was conducted in the current study (92%, 92%, and 90% for
surgery, 131I treatment, and drug treatment, respectively).

Approximately 65% of the study subjects had been treated with 131I; 25% had received 131I treatment alone and 39% had received 131I in addition to surgery and/or drugs (Table 2). The average 131 I administered activity was
6.1 mCi (SD, 5.2) per treatment. Patients treated with 131I received
1.8 treatments on average, resulting in a cumulative mean total administered
activity of 10.4 mCi (5th-95th percentile=3, 27 mCi). Both the mean number
of treatments and cumulative administered activity were higher in patients
with toxic nodular goiter (2.1 treatments and 17.0 mCi) compared with patients
with Graves disease (1.7 treatments and 10.0 mCi). The mean 131
I thyroidal uptake was 62.4% among the 20639 patients for whom an uptake value
was recorded at first examination. Slightly more than 40% of the patients
underwent surgery, almost always in conjunction with antithyroid drugs. Only
4% of the patients received drug therapy alone. Women were younger and had
surgery somewhat more frequently than men, and patients receiving surgery
or drug therapy alone were slightly younger than those treated with 131 I. Patients with Graves disease were more likely to receive 131I treatment (65% of the Graves patients) than surgery (30.7%) or
antithyroid drugs (3.8%). In contrast, 43.2% of the patients with toxic nodular
goiter received 131I therapy compared with 54.5% treated surgically
and 2.3% treated with drugs.

At the time of study entry, 1082 patients had a history of 1338 prior
cancers. Twenty-three percent of these patients died of a malignancy during
the study period. Patients treated with drug therapy alone had the highest
crude rate (39.3 in 1000 patients) of previous cancers, those treated with 131I had an intermediate rate (14.2 in 1000 patients), and those treated
surgically had the lowest rate (5.5 in 1000 patients), except for patients
with a history of prior thyroid cancer who most often were treated surgically
for their hyperthyroidism.

All Treatments

All Patients. Overall, 16683 deaths (49.4%) occurred among the 33748 patients from
the United States with known date of birth, date of study entry, and sex.
Cause of death was known for all but 111 of the deceased subjects. Cancer
was the primary cause of death for 2950 patients, whereas 2857.6 deaths from
cancer (SMR, 1.03) were expected (Table 3). The risk of death from cancer varied by years of follow-up, but
was significantly elevated only during the first 4 years (SMR, 1.31; 95% CI,
1.19-1.43), particularly during the first year (SMR, 1.52; 95% CI, 1.25-1.84).
During the entire study period, deaths from cancers of the lung (SMR, 1.11),
breast (SMR, 1.17), kidney (SMR, 1.31), and thyroid (SMR, 2.77) were significantly
elevated compared with the US population. For all 4 cancer types, the SMRs
were highest within 5 years of study entry, and only thyroid cancer mortality
remained significantly higher than expected 10 or more years after study entry
(SMR, 2.01; 95% CI, 1.10-3.37).

Mortality from cancers of the liver, larynx, uterus, and prostate occurred
significantly below expectation. No excess deaths from lymphoma, leukemia,
or hematopoietic and lymphoproliferative malignancies as a group were apparent
over the entire study period, but leukemia mortality was increased 5 to 9
years after study entry (SMR, 1.62; 95% CI, 1.01-2.45).

Because 79% of the study population was female, their mortality experience
dominates the overall evaluations. Among women, 2252 cancer deaths were observed
compared with 2101.8 expected (SMR, 1.07; 95% CI, 1.03-1.12), and an excess
of lung (SMR, 1.28; 95% CI, 1.14-1.44), breast (SMR, 1.17; 95% CI, 1.07-1.28),
kidney (SMR, 1.37; 95% CI, 1.00-1.83), and thyroid (SMR, 2.66; 95% CI, 1.70-3.95)
cancer mortality was observed. A deficit of mortality from cancers of the
uterus (corpus and cervix) also was seen (SMR, 0.67; 95% CI, 0.55-0.80). Five
or more years after study entry, only mortality from lung and thyroid cancer
remained in excess, but the deficit of deaths from cancer of the uterus was
still observed. For men, the overall risk of cancer mortality was lower than
expected (SMR, 0.92; 95% CI, 0.86-0.99). Based on only 5 deaths, the risk
of thyroid cancer was elevated (SMR, 3.51; 95% CI, 1.13-8.18), largely because
of a 14-fold excess (95% CI, 2.35-33.72) during the first 4 years of follow-up.
Deficits of laryngeal (SMR, 0.29; 95% CI, 0.006-0.83) and prostate (SMR, 0.73;
95% CI, 0.56-0.94) cancer mortality were evident.

Patients With Graves Disease and Toxic Nodular Goiter. An increase in overall cancer mortality was not associated with Graves
disease (SMR, 1.02; 95% CI, 0.98-1.06), but was 16% higher than expected among
patients with toxic nodular goiter (SMR, 1.16; 95% CI, 1.03-1.30) (Table 4). Among Graves disease patients,
mortality from cancers of the breast, kidney, and thyroid was elevated, but
again the excess risks were observed only during the first 4 years of follow-up.
Deaths from cancers of the liver, larynx, uterus, and prostate as well as
multiple myeloma were lower than expected. Among patients with toxic nodular
goiter, excess deaths from lung, breast, and thyroid malignancies were observed
and were seen 5 or more years after study entry (SMR for lung cancer, 1.46
[95% CI, 1.01-2.06]; for breast cancer, 1.45 [95% CI, 1.03-1.98]; and for
thyroid cancer, 4.3 [95% CI, 1.16-11.01]).

I Treatment

Cancer mortality relative to treatment was evaluated excluding the first
year of follow-up (Table 5). Although
almost 21000 people with over 385000 person-years of follow-up were studied,
the overall cancer risk for patients treated with 131I was close
to that expected using national cancer mortality rates (SMR, 1.02; 95% CI,
0.98-1.07). Mortality from thyroid cancer (SMR, 3.94; 95% CI, 2.52-5.86) was
raised, but mortality from cancers of the uterus and prostate was below expectation.
Among the 8054 patients treated with 131I only, findings were similar.
To ensure that the elevated thyroid cancer mortality was not due to the 4
patients who had thyroid cancer prior to entering the study, we also analyzed
the data excluding them. The SMR was still substantially increased (SMR, 3.28).

Between 1 and 5 years after follow-up, significantly elevated SMRs (Table 6) were observed for all cancer mortality
(SMR, 1.24; 95% CI, 1.10-1.40) and mortality from colorectal cancer (SMR,
1.42; 95% CI, 1.04-1.90). Deaths from lung cancer (SMR, 1.44; 95% CI, 1.13-1.81)
and non–chronic lymphatic leukemia (non-CLL) (SMR, 1.88; 95% CI, 1.18-2.84)
were in excess within the first 9 years. After 10 years of follow-up only
thyroid cancer mortality remained significantly increased. There were no observed
or expected thyroid cancer deaths among the 365 patients treated with 131I before age 20 years.

Significant relationships between the number of 131I treatments
and overall cancer mortality (SMR, 1.00, 1.09, and 0.99 for 1, 2-4, and ≥5
treatments, respectively) or individual cancer sites, except thyroid cancer,
were not observed (data not shown). Restricting the analysis to either 5 years
or 10 or more years after study entry did not modify these conclusions. The
SMRs for thyroid cancer deaths increased with increasing number of treatments
during the study period (2.74, 6.21, and 6.61 for 1, 2-4, and ≥5 treatments,
respectively), as well as for the period beginning 10 years after study entry
(2.66, 4.48, and 5.43 for 1, 2-4, and ≥5 treatments, respectively).

Table 7 provides some evidence
of a relationship between administered 131 I activity and total
cancer mortality, as well as mortality from lung and thyroid cancer. However,
at 10 or more years after study entry, the relationship with administered
activity was less notable; the SMRs for less than 7 mCi, 7-15 mCi, and 15
mCi or more administered activity were 0.90, 1.03, and 1.06, respectively,
for all cancer mortality; 0.83, 1.03, and 1.21, respectively, for lung cancer
mortality; and 1.85, 4.11, and 1.59, respectively, for thyroid cancer mortality
(data not shown). An evaluation of 131I activity by type of hyperthyroidism
indicated that thyroid cancer mortality increased with increasing administered
activity for patients with Graves disease. Among patients with toxic nodular
goiter, there was no relationship with amount of activity, but the number
of cancers was small and the CIs were wide.

The Poisson regression analyses of the relationship between administered
activity and subsequent thyroid cancer mortality, taking type of hyperthyroidism
into account, excluded patients treated surgically (because their risk of
thyroid cancer is reduced by decreasing the volume of tissue) and patients
who had cancer before study entry, leaving 16 thyroid cancer deaths (Table 8). The RR in the highest administered
activity group was 2.3 (95% CI, 0.97-9.5), but the exposure-response trend
was not statistically significant (P=.12). Similarly,
the excess RR point estimate result (excess RR at 1 mCi=0.12) was positive,
but not significant. Five or more years after study entry, no relationship
was seen between administered activity and subsequent thyroid cancer mortality.

No relationship between level of 131I administered activity
or estimated bone marrow dose and CLL, non-CLL, Hodgkin disease, non–Hodgkin
lymphoma, or multiple myeloma was demonstrated (Table 9). Because the latency period for radiation-induced non-CLL
is short, we also analyzed the non-CLL data for only the first 10 years of
follow-up, but again, no association with estimated bone marrow dose was seen
(P=.46). For multiple myeloma, the RRs were increased
in the 2 highest administrated activity and estimated bone marrow dose groups,
but the numbers were small and the dose-response trend was not significant.

Surgical Treatment

Among the 10876 patients receiving surgical treatment without 131 I, the SMR for total cancer mortality was 0.99 (Table 5). Excluding the first year of follow-up, lung and breast
cancer mortality was significantly elevated among surgical patients, but not
thyroid cancer mortality (SMR, 1.07). A 50% reduction in multiple myeloma
mortality (SMR, 0.48; 95% CI, 0.19-0.99) was observed.

Antithyroid Drug Treatment

One year or more after study entry, there was a significant increase
in the number of cancer deaths from all causes, as well as buccal and brain
cancer among patients treated with antithyroid drugs (Table 5). Because patients treated with antithyroid drugs had an
especially high rate of cancers diagnosed before study entry, an SMR analysis
excluding patients with cancers diagnosed prior to study entry was performed.
In this analysis, only brain cancer deaths remained elevated; however, excluding
patients with cancers prior to study entry will underestimate the SMR.

COMMENT

We evaluated cancer mortality following 3 treatment modalities for hyperthyroidism.
We put special emphasis on 131I therapy because it is the treatment
of choice in the United States, and the role of 131I in carcinogenesis
remains unclear. The investigators of the first evaluation of the Cooperative
Thyrotoxicosis Therapy Follow-up Study cohort reported no increased risk of
either leukemia or thyroid cancer incidence among patients treated with 131 I compared with patients treated by other methods.5,6,10,16
In contrast, Williams28 interpreted the thyroid
data as showing a slight excess of anaplastic thyroid cancer among the group
treated with 131I, which he hypothesized might be caused by radiation-induced
progression from undetected differentiated carcinomas to undifferentiated
carcinomas. Additional follow-up of 2 subgroups of female patients from the
original cohort suggested that there might be a slight increased risk of cancers
occurring in organs known to concentrate 131 I11,13
or of breast cancer incidence.14

In the present follow-up, 131I treatment did not result in
a larger-than-expected number of deaths due to cancer when compared with US
age-, sex-, and calendar-year–specific mortality rates. No excess mortality
was observed when cancer in organs that concentrate 131 I (salivary,
esophagus, stomach, colon, rectum, liver, bladder, and kidney) were grouped
together (SMR, 1.03). A detailed analysis of hematopoietic malignancies revealed
that neither 131 I administered activity nor estimated bone marrow
dose were associated with mortality from non-CLL. This lack of positive results
is not unexpected because the mean doses to all organs, except for the thyroid
gland, which received extremely large doses, were below 200 mGy. At such low
doses the statistical power to detect effects is limited. Because the study
population was almost entirely adult, the results, however, cannot be generalized
to childhood exposure.

Mortality studies are not well suited for studying thyroid cancer. Nonetheless,
we did observe a significantly increased rate of thyroid cancer mortality
among men and women and among patients with toxic nodular goiter or Graves
disease. The elevated risk of thyroid cancer mortality was seen only for patients
treated with 131I. Using either an external (SMR analysis) or internal
(Poisson analysis) comparison, the risk appeared to increase with increasing
amounts of 131 I administered activity. The trend was not significant
more than 10 years after study entry, or in the analysis using the internal
comparison.

Several points should be noted in interpreting these results. The correlation
between the amount of administered activity and thyroid radiation dose generally
is poor in patients with hyperthyroidism22;
patients receiving higher 131 I activity generally had more severe
disease and frequently had relapses; patients dying from thyroid cancer were
more likely to have had toxic nodular goiter than Graves disease (30% vs 8%);
the major increase in mortality was seen in the first 5 years after treatment;
goiter, particularly nodular goiter, has been reported as a risk factor for
thyroid cancer29- 31;
and some of the patients with toxic nodular goiter may have had an undiagnosed
preexisting thyroid cancer when they entered the study.

If it is assumed that the observed excess of thyroid cancer is causal,
the risk would be smaller than the risks observed following external radiation.
Some of the difference may be explained by 131I therapy-induced
cell killing. Although thyroid doses could not be estimated directly, the
aim of 131I treatment for hyperthyroidism is to destroy the thyroid.32 The effectiveness of 131I in killing thyroid
cells presumably reduces the likelihood of malignant cell transformation.
Another explanation may be related to age at exposure. Since the risk of developing
thyroid cancer after external irradiation decreases with increasing age at
exposure, with little risk demonstrated after age 20 years, data from this
study of adults are insufficient to allow relevant comparisons between 131I and external radiation. To date, almost all human data on 131I are from populations exposed as adults,15,33- 37
whereas most data from external radiation exposure to the thyroid are from
individuals treated during childhood.38,39
Finally, some patients treated with 131I in this study had full
or partial thyroidectomies later, which might have lowered the risk of subsequent
thyroid cancer by removing radiation-damaged tissue.

Compared with our study, the patients in a Swedish mortality series15 were slightly older, had 4 fewer years of follow-up,
and had a higher percentage of patients with toxic nodular goiter and consequently
a larger mean total 131I administered activity. The SMR for total
cancer mortality was close to expected in both studies and, with the exception
of thyroid cancer, the SMRs for other cancers were between 0.8 and 1.3. Although
the increased risk of digestive tract and respiratory cancer mortality reached
significance in the Swedish study, the risks were only 10% and 30% higher
than expected, respectively. In our study, we did observe an increased risk
of respiratory cancer mortality among patients with toxic nodular goiter treated
with 131I. Differences between the 2 studies easily could be caused
by the higher proportion of Swedish patients with toxic nodular goiter or
due to chance.

This study is unique because of its large size and its inclusion of
patients not treated with 131I. In the present follow-up, small
but significant increases in breast, lung, and kidney cancer mortality were
observed in the entire cohort of hyperthyroid patients compared with the general
population. Smoking, lifestyle, and reproductive histories were not known,
and these factors could confound the results. Because much of the elevated
mortality occurred during the first few years of follow-up, underlying disease
may be responsible for some of the excess. Although the group of patients
treated with antithyroid drugs was small, the observed cancer mortality for
several sites (total cancer, buccal, stomach, breast, and brain) was higher
than expected compared with national rates. Analyses excluding patients with
previous cancers suggested that some, but not all, of the excess could be
attributed to the selection of patients for drug therapy. Patients treated
with drugs mainly received thiourea derivatives, iodine compounds, or a combination
of the 2, but sometimes received various other drugs. The type, quantity,
and dates of drug use generally were not available from the medical charts
and could not be taken into consideration in the analysis. Because the quality
of the drug data in this study is clearly limited, long-term effects of antithyroid
drugs need to be evaluated further.

Although the study has several strengths, it also has limitations. First,
thyroid doses could not be estimated and exposure response was based on 131I administered activity. Second, mortality is not the ideal study
end point. Causes of death, as listed on death certificates, frequently are
inaccurate and rarely mention the histological type of cancer. In addition,
information on cancers with high survival rates such as thyroid and breast
is limited. Third, about 20 cancer sites were evaluated by latency, type of
hyperthyroidism, treatment group, and for patients treated with 131
I, amount of administered activity. By conducting multiple comparisons, the
probability of incorrectly rejecting a null hypothesis increases and suggests
cautious interpretation of these data. On the other hand, the small number
of patients and deaths in many of the subgroup analyses and the low radiation
doses to most organs, other than the thyroid, limit the power to detect significant
risks. Finally, patients are selected for a specific treatment based on their
medical condition. For example, patients undergoing surgery were less likely
to have had a previous cancer (except of the thyroid) than patients treated
with drugs or 131I. Thus, comparing risks related to treatment
is problematic.

In summary, in a large series of hyperthyroid patients followed up for
nearly a lifetime, cancer mortality was not significantly elevated. High-dose
therapeutic 131I administration, the most frequent treatment, also
was not linked to an excess of total cancer mortality. Although a small number
of thyroid cancer deaths might be attributed to 131I therapy, overall,
it appears to be a safe therapy.

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